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Monogenic Hypertension

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Hypertension in Children and Adolescents

Part of the book series: Updates in Hypertension and Cardiovascular Protection ((UHCP))

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Abstract

Blood pressure is regulated by many hormonal, neural, and autacoid systems which are under influence of genes controlling the structure of the vascular bed, peripheral blood flow, and water and electrolyte homeostasis. Single polymorphisms of these genes may predispose to arterial hypertension (AH) but are not sufficient to induce AH without additional stimuli and may explain blood pressure variability in only a small percentage. However, some rare forms of AH are caused by mutation of one gene and are inherited according to Mendelian principles. These mutations involve genes regulating basic mechanisms of peripheral blood flow and/or electrolyte metabolism. Clinical presentation includes a full spectrum of symptoms from a symptomless carrier state to AH in adulthood up to severe AH developing in the first months of life. All but one form of monogenic hypertension are related to disturbances of sodium excretion/reabsorption in the kidneys, and only one is sodium independent and caused by primary increase of peripheral arterial resistance. The diagnosis can be suspected based on careful clinical observation of intermediate phenotype and confirmed by molecular analysis. Early diagnosis enables targeted treatment and allows achievement of normotension.

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References

  1. Vehaskari VM. The heritable forms of hypertension. Pediatr Nephrol. 2009;24:1929–37.

    Article  Google Scholar 

  2. Toka O, Maas PG, Aydin A, Toka H, Hübner N, Rüschendorf F, Gong M, Luft FC, Bähring S. Childhood hypertension in autosomal dominant brachydactyly with hypertension. Hypertension. 2010;56:988–94.

    Article  CAS  Google Scholar 

  3. Toka O, Tank J, Schächterle C, Aydin A, Maass PG, Elitok S, et al. Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly. Hypertension. 2015;66:800–8.

    Article  CAS  Google Scholar 

  4. Bähring S, Kann M, Neuenfeld Y, Gong M, Chitayat D, Toka HR, et al. Inversion region for hypertension and brachydactyly on chromosome 12p features multiple splicing and noncoding RNA. Hypertension. 2008;51(2):426–31.

    Article  Google Scholar 

  5. Luft FC, Toka O, Toka HR, Jordan J, Bahring S. Mendelian hypertension with brachydactyly as a molecular lesson in regulatory physiology. Am J Physiol Regul Integr Comp Physiol. 2003;285:R709–14.

    Article  CAS  Google Scholar 

  6. Monticone S, Buffolo F, Tetti M, Veglio F, Pasini B, Mulatero P. Genetics in endocrinology: the expanding genetic horizon of primary aldosteronism. Eur J Endocrinol. 2018;178(3):R101–R11.

    Article  CAS  Google Scholar 

  7. Scholl UI, Goh G, Stölting G, de Oliveira RC, Choi M, Overton JD, et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet. 2013;45(9):1050–4.

    Article  CAS  Google Scholar 

  8. Ko B, Hoover RS. Molecular physiology of the thiazide-sensitive sodium chloride cotransporter. Curr Opin Nephrol Hypertens. 2009;18:421–7.

    Article  CAS  Google Scholar 

  9. O’Shaughnessy KM. Gordon syndrome: a continuing story. Pediatr Nephrol. 2015;30:1903–8.

    Article  Google Scholar 

  10. Bazúa-Valenti S, Gamba G. Revisiting the NaCl cotransporter regulation by with-no-lysine kinases. Am J Physiol Cell Physiol. 2015;308:C779–91.

    Article  Google Scholar 

  11. Botero-Velez M, Curtis JJ, Warncock DG. Liddle’s syndrome revisited: a disorder of sodium reabsorption in the distal tubule. N Engl J Med. 1994;330:178–81.

    Article  CAS  Google Scholar 

  12. Findling JW, Raff H, Hansson JH, Lifton R. Liddle’s syndrome: prospective genetic screening and suppressed aldosterone secretion in an extended kindred. J Clin Endocrinol Metab. 1997;82:1071–4.

    CAS  PubMed  Google Scholar 

  13. Jin HS, Hong KW, Hwang SY, Lee SH, Shin C, Park HK, Oh B. Genetic variations in the sodium balance-regulating genes ENaC, NEDD4L, NDFIP2 and USP2 influence blood pressure and hypertension. Kidney Blood Press Res. 2010;33:15–23.

    Article  CAS  Google Scholar 

  14. Baker EH, Dong YB, Sagnella GS, Rothwell M, Onipinla AK, Markandu ND, et al. Association of hypertension with T594M mutation in beta subunit of epithelial sodium channel. Lancet. 1998;351:1388–92.

    Article  CAS  Google Scholar 

  15. Wong YH, Stebbing M, Ellis JA, Lamantia A, Harrap SB. Genetic linkage of beta and gamma subunits of epithelial sodium channel to systolic blood pressure. Lancet. 1999;353:122–1225.

    Article  Google Scholar 

  16. Araki N, Umemura M, Miyagi Y, Yabana M, Miki Y, Tamura K, et al. Expression, transcription and possible antagonistic interaction of the human NEDD4L gene variant. Implications for essential hypertension. Hypertension. 2008;51:773–7.

    Article  CAS  Google Scholar 

  17. Luo F, Wang Y, Wang X, Sun K, Zhou X, Hui R. A functional variant of NEDD4L is associated with hypertension, antihypertensive response, and orthostatic hypotension. Hypertension. 2009;54:796–801.

    Article  CAS  Google Scholar 

  18. Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science. 2000;289:119–23.

    Article  CAS  Google Scholar 

  19. Huyet J, Pinon GM, Fay MR, Rafestin-Oblin ME, Fagart J. Structural determinants of ligand binding to the mineralocorticoid receptor. Mol Cell Endocrinol. 2012;350(2):187–95.

    Article  CAS  Google Scholar 

  20. Werder EA, Zachmann M, Vollmin JA, Veyrat R, Prader A. Unusual steroid excretion in a child with low renin hypertension. Res Steroids. 1974;6:385–9.

    Google Scholar 

  21. New MI, Levine LS, Biglieri EG, Pareira J, Ulick S. Evidence for an unidentified ACTH-induced steroid hormone causing hypertension. J Clin Endocrinol Metab. 1977;44:924–33.

    Article  CAS  Google Scholar 

  22. New MI, Oberfield SE, Carey RM, Greig F, Ulick S, Levine LS. A genetic defect in cortisol metabolism as the basis for the syndrome of apparent mineralocorticoid excess. In: Mnatero F, Biglieri EG, Edwards CRW, editors. Endocrinology of hypertension. Serono Symposia No. 50. New York: Academic; 1982.

    Google Scholar 

  23. Atanasov AG, Ignatova ID, Nashev LG, Dick B, Ferrari P, Frey FJ, Odermatt A. Impaired protein stability of the 11 beta hydroxysteroid dehydrogenase type 2: a novel mechanism of apparent mineralocorticoid excess. J Am Soc Nephrol. 2007;18:1262–70.

    Article  CAS  Google Scholar 

  24. Morineau G, Sulmont V, Salomon R, Fiquet-Kempf B, Jeunemaître X, Nicod J, Ferrari P. Apparent mineralocorticoid excess: report of six new cases and extensive personal experience. J Am Soc Nephrol. 2006;17:3176–84.

    Article  CAS  Google Scholar 

  25. Li A, Li KXZ, Marui S, Krozowski ZS, Batista MC, Whorwood CB, et al. Apparent mineralocorticoid excess in Brazilian kindred: hypertension in the heterozygote state. J Hypertens. 1997;15:1397–402.

    Article  CAS  Google Scholar 

  26. Li A, Tedde R, Krozowski ZS, Pala A, Li KX, Shackleton CH, et al. Molecular basis for hypertension in the “type II” variant of apparent mineralocorticoid excess. Am J Hum Genet. 1998;63:370–9.

    Article  CAS  Google Scholar 

  27. Ferrari P, Lovati E, Frey FJ. The role of 11 beta hydroxysteroid dehydrogenase type 2 in human hypertension. J Hypertens. 2000;18:241–8.

    Article  CAS  Google Scholar 

  28. Lo YH, Sheff MF, Latif SA, Silver H, Brem AS, Morris DJ. Kidney 11 beta HSD2 is inhibited by glycerrhetinic acid-like factors in human urine. Hypertension. 1997;29:500–5.

    Article  CAS  Google Scholar 

  29. Baserga M, Kaur R, Hale MA, Bares A, Yu X, Callaway CW, et al. Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11 beta hydroxysteroid dehydrogenase type 2 in a sex-specific manner. Am J Physiol Regul Integr Comp Physiol. 2010;299:R334–42.

    Article  CAS  Google Scholar 

  30. Cottrell EC, Seckl JR, Holmes MC, Wyrwoll CS. Foetal and placental 11β-HSD2: a hub for developmental programming. Acta Physiol (Oxf). 2014;210(2):288–95.

    Article  CAS  Google Scholar 

  31. Morton NM. Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Mol Cell Endocrinol. 2010;25:154–64.

    Article  Google Scholar 

  32. Paver WK, Pauline GJ. Hypertension and hyperpotassaemia without renal disease in a young male. Med J Aust. 1964;2:305–6.

    CAS  PubMed  Google Scholar 

  33. Gordon RD, Geddes RA, Pawsey CGK, O’Halloran MW. Hypertension and severe hyperkalaemia associated with suppression of renin and aldosterone and completely reversed by dietary sodium restriction. Aust Ann Med. 1970;4:287–94.

    Google Scholar 

  34. Pathare G, Hoenderop JG, Bindels RJ, San-Cristobal P. A molecular update on pseudohypoaldosteronism type II. Am J Physiol Renal Physiol. 2013;305(11):F1513–20.

    Article  CAS  Google Scholar 

  35. Sohara E, Uchida S. Kelch-like 3/Cullin 3 ubiquitin ligase complex and WNK signaling in salt-sensitive hypertension and electrolyte disorder. Nephrol Dial Transplant. 2016;31(9):1417–24.

    Article  CAS  Google Scholar 

  36. Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature. 2012;482(7383):98–102.

    Article  CAS  Google Scholar 

  37. Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, et al. International Consortium for Blood Pressure (ICBP), Bruneval P, Estivill X, Froguel P, Hadchouel J, Schott JJ, Jeunemaitre X. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet. 2012;44(4):456–60.. S1-3

    Article  CAS  Google Scholar 

  38. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006;48:2293–300.

    Article  CAS  Google Scholar 

  39. Korahet HE, Scholl UI. An update on familial hyperaldosteronism. Horm Metab Res. 2015;47(13):941–6.

    Article  Google Scholar 

  40. Stowasser M, Bachmann AW, Huggard PJ, Rossetti TR, Gordon RD. Treatment of familial hyperaldosteronism type I: only partial suppression of hybrid gene required to correct hypertension. J Clin Endocrinol Metab. 2000;85:3313–8.

    Article  CAS  Google Scholar 

  41. Stowasser M, Gordon RD, Tunny TJ, Klemm SA, Finn WL, Krek AL. Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism. Clin Exp Pharmacol Physiol. 1992;19(5):319–22.

    Article  CAS  Google Scholar 

  42. Scholl UI, Stölting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, et al. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet. 2018;50(3):349–54.

    Article  CAS  Google Scholar 

  43. Fernandes-Rosa FL, Daniil G, Orozco IJ, Göppner C, El Zein R, Jain V, et al. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nat Genet. 2018;50(3):355–61.

    Article  CAS  Google Scholar 

  44. Geller DS, Zhang J, Wigerhof MV, Schackelton C, Kashagarian M, Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid–remediable aldosteronism. J Clin Endocrinol Metab. 2008;93:3117–23.

    Article  CAS  Google Scholar 

  45. Monticone S, Tetti M, Burrello J, Buffolo F, De Giovanni R, Veglio F, Williams TA, Mulatero P. Familial hyperaldosteronism type III. J Hum Hypertens. 2017;31(12):776–8.

    Article  CAS  Google Scholar 

  46. Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, et al. K channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331:768–72.

    Article  CAS  Google Scholar 

  47. Monticone S, Bandulik S, Stindl J, Zilbermint M, Dedov I, Mulatero P, et al. A case of severe hyperaldosteronism caused by a de novo mutation affecting a critical salt bridge Kir3.4 residue. J Clin Endocrinol Metab. 2015;100(1):E114–8.

    Article  CAS  Google Scholar 

  48. Scholl UI, Stölting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, et al. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. elife. 2015;4:e06315.

    Article  Google Scholar 

  49. Chrousos GP, Vingerhoeds A, Brandon D, Eil C, Pugeat M, DeVroede M, et al. Primary cortisol resistance in man. A glucocorticoid receptor mediated disease. J Clin Invest. 1982;69:1261–9.

    Article  CAS  Google Scholar 

  50. Chrousos GP, Detera-Wadleigh SD, Karl M. Syndromes of glucocorticoid resistance. Ann Intern Med. 1993;119:1113–24.

    Article  CAS  Google Scholar 

  51. Nader N, Bachrach BE, Hurt DE, Gajula S, Pittman A, Lescher R, Kino T. A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain. J Clin Endocrinol Metab. 2010;95(5):2281–5.

    Article  CAS  Google Scholar 

  52. Nicolaides NC, Charmandari E. Chrousos syndrome: from molecular pathogenesis to therapeutic management. Eur J Clin Invest. 2015;45(5):504–14.

    Article  CAS  Google Scholar 

  53. Bilginturan N, Zileli S, Karacadag S, Pirnar T. Hereditary brachydactyly associated with hypertension. Am J Med Genet. 1973;10:253–9.

    Article  CAS  Google Scholar 

  54. Naraghu R, Schuster H, Toka HR, Bähring S, Toka O, Oztekin O, et al. Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension with brachydactyly. Stroke. 1997;28:1749–54.

    Article  Google Scholar 

  55. Schuster J. Autosomal dominant hypertension with brachydactyly: an enigmatic form of monogenic hypertension. Nephrol Dial Transplant. 1998;13:1337–49.

    Article  CAS  Google Scholar 

  56. Schuster H, Toka O, Toka HR, Busjahn A, Oztekin O, Wienker TF, et al. A crossover medication trial for patients with autosomal dominant hypertension with brachydactyly. Kidney Int. 1998;53:167–72.

    Article  CAS  Google Scholar 

  57. Jannetta PJ, Segal R, Wolfson SK Jr. Neurogenic hypertension: etiology and surgical treatment. I. Observations in 53 patients. Ann Surg. 1985;201(3):391–8.

    Article  CAS  Google Scholar 

  58. Jannetta PJ, Segal R, Wolfson SK Jr, Dujovny M, Semba A, Cook EE. Neurogenic hypertension: etiology and surgical treatment I. Observations in an experimental model of nonhuman primate model. Ann Surg. 1985;201:254–61.

    Article  Google Scholar 

  59. Litwin M, Jurkiewicz E, Nowak K, Kościesza A, Grenda R, Malczyk K, Kościesza I. Arterial hypertension with brachydactyly in a 15 years old boy. Pediatr Nephrol. 2003;18:814–9.

    Article  Google Scholar 

  60. Derbent M, Baskin E, Agildere M, Agras PI, Saatçi U. Brachydactyly short stature hypertension syndrome: a case with associated vascular malformations. Pediatr Nephrol. 2006;21:390–3.

    Article  Google Scholar 

  61. Maass PG, Aydin A, Luft FC, Schächterle C, Weise A, Stricker S, et al. PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nat Genet. 2015;47(6):647–53.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Nephrology and Arterial Hypertension, The Children’s Memorial Health Institute, Warsaw, Poland

    Mieczysław Litwin

  2. Division of Nephrology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada

    Janusz Feber

  3. Department of Clinical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland

    Elżbieta Ciara

Authors
  1. Mieczysław Litwin
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  2. Janusz Feber
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  3. Elżbieta Ciara
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Correspondence to Mieczysław Litwin .

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Editors and Affiliations

  1. Head of Pediatrics Department, Hospital General Universitario Valencia, Valencia, Spain

    Empar Lurbe

  2. Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany

    Elke Wühl

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Litwin, M., Feber, J., Ciara, E. (2019). Monogenic Hypertension. In: Lurbe, E., Wühl, E. (eds) Hypertension in Children and Adolescents. Updates in Hypertension and Cardiovascular Protection. Springer, Cham. https://doi.org/10.1007/978-3-030-18167-3_9

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  • DOI: https://doi.org/10.1007/978-3-030-18167-3_9

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